The Eph family of receptor tyrosine kinases and their membrane-bound ligands, the ephrins, have been implicated in regulating cell adhesion and migration during development by mediating cell-to-cell signaling events. We have shown that ectopic expression of X-ephrinB1, a Xenopus homologue of the murine ephrin-B1 transmembrane ligand, causes dissociation of Xenopus embryonic blastomeres by the mid-blastula transition. Moreover, a mutant which lacks the extracellular receptor binding domain can induce this phenotype. Basic fibroblast growth factor (bFGF), but not activin, can rescue both the loss of cell adhesion and mesoderm induction in ectodermal explants expressing ephrinB1. Genetic evidence from other laboratories suggests that ephrins may transduce signals, and become tyrosine phosphorylated during embryogenesis. However, the induction and functional significance of ephrin phosphorylation is not yet clear. Our studies reveal that an activated fibroblast growth factor (FGF) receptor associates with and phosphorylates ephrinB1 on tyrosine. Moreover, this phosphorylation is a regulatory event that alters ephrinB1 function in cell adhesion. In addition, we identify a region in the cytoplasmic tail of ephrinB1 that is critical for direct interaction with the FGF receptor. We also find that FGF treatment of neural tissue expressing ephrinB1 reduces cell binding to a cognate Eph receptor substrate. This is the first demonstration of direct communication between the FGF receptor family and the Eph ligand family and implicates crosstalk between these two cell surface molecules in regulating cell adhesion. Another Eph family member that has been the focus of our work is the EphA4 receptor tyrosine kinase that has been shown to be important for rhombomeric integrity, and proper neural crest movement. EphA4 has an expression pattern that overlaps with EphrinB1 during development. When ectopically expressed in Xenopus embryos, an activated EphA4 receptor affects similar adhesive events as observed for ephrinB1. Within the cytoplasmic domain of EphA4, several molecules including Fyn, PLC-gamma, Nck, Ephexin (a Rho-like guanine nucleotide exchange factor), and low molecular weight protein tyrosine phosphatase (LMW-PTP) have been proposed or shown to bind various domains and residues such as the juxtamembrane tyrosines, a sterile alpha motif (SAM), and a PDZ binding motif. We have been examining the contribution of certain structural motifs to the biochemical and developmental activities elicited by the EphA4 receptor.